Process for the production of new picolinic acid derivatives



United States Patent 3,228,950 PROCESS FDR THE PRODUCTION OF NEWPICOLINIC ACID DERIVATIVES Ernst F. Renk, lm Langen L011 190, Basel,Switzerland, and Niels Clauson-Kaas, Rugmarken 28, Farum, Denmark NoDrawing. Filed Nov. 4, 1963, Ser. No. 322,000 Claims priority,application Switzerland, Nov. 9, 1962, 13,166/62 Claims. (Cl. 260-295)The present invention relates to a new process for the production ofpicolinic acid derivatives as well as the compounds obtainable accordingto this process, which are especially useful as intermediates formedicaments.

According to a first aspect of the invention the novel3-hydroxy-N-nitro-picolinamide, of the formula is produced by treatingthe 3-hydroxy-picolinamide with a nitric acid-sulfuric acid mixture at atemperature of not higher than about 25 C.

This is unexpected, for, whereas the nitration of the arylsulfonic acidamides, which are unsubstituted in the amide group, and of the carbonicacid amides such as ureas and urethanes, is a known reaction, only thenitration of N-substituted amides has been successfully performed in theseries of the carboxylic acid amides (see W. E. Bachmann et al., I. Am.Chem. Soc. 72, 3132 [1950] and E. A. White et al., I. Am. Chem. Soc. 831191 [1961] The only known carboxylic acid-N-nitroamides not havingfurther N-substituents, i.e. o-methoxy-carbonyl-N- nitro-benzamide,,6-methoxycarbonyl-N-nitro-propionarnide (see H. Kaufman and A. Burger,I Org. Chem. 19, 1663 [1954]) and o-ethoxysulfonyl-N-nitrobenzamide (seeI. Runge und W. Treibs, I. Pr. Chem. 286, 223 [1962] were obtained byalcoholyzing the corresponding N-nitro-imides, namely fromN-nitro-phthalimide, -succinimide and -o-sulfobenzoic acid imide resp.,and not by any method of direct nitration.

It is all the more surprising that 3-hydroxy-N-nitro-picolinamide can beproduced by the simple easily controlled p rocess according to theinvention, especially in view of t:' e fact that, when according to afrequently used nitration method, nitric acid in acetic anhydride (seeW. E. Bechmann et al., loc. cit.) is caused to react with 3-hydroxy-picolinamide, a violent reaction occurs which is difficult tocontrol.

In order to perform the above-mentioned step of the reaction sequenceaccording to the invention, 3-hydroxypicolinamide is dissolved inconcentrated sulfuric acid and a mixture of fuming nitric acid andsulfuric acid is added drop by drop while stirring, and, at the sametime, sufficient cooling to prevent the temperature of the reactionmixture from rising above 25 C. The reaction is allowed to continue fornot longer than 5 hours, after which period of time the N-nitro-amide isprecipitated, for example, by decomposing the reaction mixture with ice,and the N- nitro-amide is thus ready for direct, further use. Thenitration reaction can also be performed at a temperature below 25 C.,for example betw en 5 C. and 0 C.

While nitramides are usually highly unstable substances and hydrolyzeeasily, the compound of Formula I is surprisingly completely stableunder normal conditions and is, especially, crystallizable from water.

ice

According to a further aspect of the invention, picolinic acldderivatives of the general formula wherein R represents hydrogen, alower alkyl radical or a lower alkylene radical which forms a ring withR and the adjacent nitrogen atom, and R represents a monovalentaliphatic or cycloaliphatic radical with at most 12 carbon atoms, whichmay also contain halogen, oxygen atoms in the form of hydroxyl, ether orcarbalkoxy groups, sulfur atoms in the form of alkylthio groups, ornitrogen atoms in the form of nitrile, amide or amino groups, or aphenyl, phenylalkyl, phenoxyalkyl, phenylalkenyl, heterocyclyl orheterocycylalkyl radical with at most 12 carbon atoms, whereby thearomatic homoand hetero-rings may be substituted, if desired, by at most3 substituents from the series of alkyl groups, alkoxy groups, halogenatoms, trifiuoromethyl groups, hydroxyl groups, mercapto groups, nitrogroups and/or amino groups, or finally it represents anN-alkyl-N-phenyl-carbamoylalkyl 01' a piperidinocarbonylalkyl group within all at most 12 carbon atoms, are produced by reacting the3-hydroxy-N-nitropicolinamide (Formula I), resulting from the processstep, described hereinbefore under the first aspect of this invention,with an amine of the general formula R2 (III) in which R and R have themeaning given above, which reaction is carried out in various organicsolvents, e.g. in ethanol or dimethylformamide, or in an excess of theamine to be reacted. Reaction begins at room temperature or at a highertemperature up to C., depending on the amine to be reacted; however,reaction temperatures of above 150 should be avoided in order to preventdecomposition of the nitroamide. Self-heating of the mixture resultingfrom the exothermic salt formation of the N-nitro-amide reacting as acidwith the amine, can be observed before the reaction starts even at lowtemperatures so that, in the most favourable case, an initialtemperature of 0 C. for the reaction components is suflicient for thereaction to take its course.

The reaction of 3-hydroxy-N-nitro-picolinamide with amines of thegeneral formula III is accompanied by the development of gaseous nitrousoxide. The beginning and end of the reaction are, therefore, easilydeterminable.

N-alkyland the like substituted carboxylic acid N-nitroamides, e.g.those of acetic and oxalic acid have been split by means of ammonia intocarboxylic acid amide and N-nitro-amines for the purpose of preparingthe latter substances (see, e.g. W. Bachmann et al., loc. cit.). It was,therefore, particularly unexpected that 3-hydroxy-N-nitropicolinamidewhich is produced according to the invention and which is not furthersubstituted in the amide group, would react with primary and secondaryamines with formation of the picolinamides of Formula II and nitrousoxide.

The compounds produced according to the invention of the general FormulaII are valuable intermediates. Especially, those compounds having ahydrogen atom as R and wherein R is alkyl having maximally 12 carbonatoms, alkenyl with 3 to 4 carbon atoms, propargyl, cycloalkyl,carbethoxymethyl, p-hydroxyethyl, B-chloroethyl, 'y-hydroxypropyl,cyanomethyl, ,B-cyanoethyl, fl-carbethoxyethyl, a-carbethoxyethyl,-carbethoxypropyl, B-ethoxyethyl, ,8 methylthioethyl, 'ydirnethyl-aminopropyl, N,N-dimethylcarbamoylmethyl, phenyl,chlorophenyl, tolyl, anisyl, benzyl, methylbenzyl, dimethyl-benzyl,tert. butylbenzyl, chlorobenzyl, dichlorobenzyl, fluorobenzyl,trifluoromethylbenzyl, methoxybenzyl, dimethoxybenzyl, trimethoxybenzyl,nitrobenzyl, aminobenzyl, hydroXybenzyl, fi-phenethyl,fi-nitrophenethyl, 3-aminophenethyl, fl-phenoxyethyl, 'y-phenylpropyl,'y-m'trophenylpropyl, 'yphenyl-B-propenyl, 'y-phenoxypropyl,N-phenyl-N-methylcarbamoylmethyl, Z-thenyl, Z-furylmethyl,2-(nitrofuryl)- methyl, ,B-piperidinoethyl, piperidinylmethyl, N -loweralkyl substituted l-piperazinyl ethyl, piperidinocarbonylmethyl,pyridylmethyl or fi-pyridylethyl, are useful as intermediates in theproduction of medicaments for they can be reacted with low chloroformicacid-alkyl esters or with a chloroformic acid-phenyl ester to3-substituted 2H- pyrido-[2,3-e]oxazine-2,4(3H)-diones of the formulawherein R is hydrogen or lower alkyl having at most 3 carbon atoms, andR has the meaning given above. The compounds of Formula IV have valuablepharmacological properties, in particular analgetic, antipyretic,antiphlogistic, muscle-relaxing and also bacteriostatic and fungistaticactivity, as well as an inhibitory action on monoaminooxidase;furthermore, they are valuable intermediates in the production of otherpharmacologically active substances and also of pest control agents.

The following can be considered as radicals R alkyl radicals such as,e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl,amyl radicals etc. up to dodecyl radicals, alkenyl radicals such as e.g.allyl or crotyl radicals, alkinyl radicals such as e.g. the progargylradical, cycloalkyl radicals such as e.g. cyclopentyl, cyclohexyl orcycloheptyl radicals; further, aliphatic radicals containing halogensuch as e.g. B-chloroethyl, hydroxyalkyl, radicals such as, for instancefi-hydroxyethyl, B-hydroxypropyl, y-hydroxypropyl radicals,carbalkoxyalkyl radicals such as e.g. carbethoxymethyl, ocandfl-carbethoxyethyl and -carbethoxypropyl radicals; further, alkoxyalkylradicals such as e.g. fl-methoxyethyl as well as B-ethoxyethyl radicalsor the corresponding thioanalogs such as e.g. the ,B-methylthioethylradical, further, cyanomethyl, fi-cyanoethyl, fi-aminoethyl,y-aminopropyl, 'y-dimethylaminopropyl and N,N-dimethylcarbamoyl-methylradicals. The following types are included in the radical R whichcontain an aromatic ring: phenyl or benzyl radicals which can besubstituted, if desired, by 1-3 halogen atoms, low alkyl or alkoxyradicals and/ or the hydroxyl, mercapto, amino, nitro or thetrifiuoromethyl groups, such as e.g. an

'o-, mor p-chlorophenyl radical, a p-bromo-phenyl radical, a 2,4-, 3,4-or 2,5-dichlorophenyl radical, a p-nitro-phenyl a 3,5-dimethylbenzylradical, an o-, mor p-fluorobenzyl Y radical, a m-trifluoromethyl-benzylradical, an o-, mor p-methoxybenzyl radical, a 3,4-dimethoxy or3,4,5-trimethoxybenzyl radical, an o-, mor p-nitrobenzyl radical, an o-,mor p-aminobenzyl radical, an o-, mor p-hydroxybenzyl radical; inaddition, a ,B-phenoxyethyl or a 'yphenoxypropyl radical; further, afi-phenylethyl or a -phenylpropyl radical the benzene ring of which maybe substituted by nitro or amino groups, a =y-phneyl-[3 pr0peny1 radicalor an N-phenyl-N-methyl-carbamoymethyl radical.

The following may be mentioned as examples of heterocyclyl andheterocyclylalkyl radicals: 2, 3- and 4- pyridyl-radicals, a 4methyl-2-pyrimidyl-2,4-dimethyl-6- pyrimidyl, 4,6-dimethyl-2-pyrimidyl,3-methyl-5-isoxalyl, 2-thiazolyl or 4-methyl-2-thiazolyl radical or2-thenyl or 2-furylmethyl radicals the rings of which may also besubstituted by a nitro group, respectively; further piperidinoalkylradicals such as a fi-piperidinoethyl radical, 4- substitutedpiperazinyl-(l)-alkyl radicals such as, for example, a,9-(4-methyl-l-piperazinyl)ethyl radicals, as well as pyridylalkylradicals such as e.g. 2- and 4-pyridylmethyl or [3-(2 and4-pyridyl)-ethy1 radicals.

R is, for example, hydrogen, a methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec. butyl, n-amyl, isoamyl or n-hexyl radical.

When. R and R are bound together, they form, together with the nitrogenatom to which they are linked, e.g. the l-pyrrolidinyl, piperidino,hexamethyleneimino, morpholine, 4-methyl-l-piperazinyl, l-indolinyl orl,2,3,4- tetrahydrol-quinolyl radical.

Another group of intermediates according to the invention, which fallalso under the general formula of the end products obtainable by thesecondprocess step according to the invention, are those of the formulawherein X is OH, --SH, NH or --NH-lower alkyl, and

Y represents chlorine, bromine, fluorine, nitro, lower alkyl or loweralkoxy. These compounds of Formula V are produced from3hydroxy-N-nitro-picolinamide and an amine of the formula wherein X andY have the meaning given above, under the reaction conditions describedhereinbefore in the second reaction step according to the invention.

The compounds of Formula V are useful as intermediates in the productionof fungistatic, tuberculostatic and analgetically-active compounds offormula wherein X is O, S, NH or N-lower alkyl, which result from thecompounds of Formula V by dehydrolysisz through heating at about 150 to250 C. under evapora-- tion of the water formed.

The following non-limitative examples illustrate the invention in moredetail. The temperatures are given in degrees Centigrade. Percentagesare given by weight.

Example I 150 grams (g.) of 3-hydroxy-picolinamide are added in portionsto 300 milliliters (ml.) of concentrated sulfuric acid, whereby coolingprevents the temperature from rising above 20. A mixture of ml. offuming nitric acid and 75 ml. of concentrated sulfuric acid is thenadded dropwise to the solution while stirring and 5 taking care that thetemperature does not exceed 25. The reaction mixture is left to standfor a further 5 hours at about 20", it is then poured onto ice and theprecipitated yellow crystals are filtered. After washing with a largequantity of water and acetone, 3-hydroxy- N-nitro-picolinamide isobtained as a yellow substance having a melting point of ca. 206(decomposition). Yield: 75% of the theoretical.

Example 2 50 g. of 3-hydroxy-picolinamide are added in portions at 10-15to 100 ml. of concentrated sulphuric acid while stirring. After coolingto 5, a mixture of 40 ml. of fuming nitric acid and 25 ml. ofconcentrated sulphuric acid is added dropwise while stirring at 5 to Thereaction mixture is then stirred for a further hour at 0 and poured ontoice. The precipitated 3-hydroxy-N- nitro-picolinamide is filtered andwashed first with 2 N sulphuric acid, then with water and finally withacetone. Yield: 70% of the theory.

Example 3 5 ml. of a 33% ethanolic methylamine solution are added to asuspension of 2.50 g. of 3-hydroxy-N-nitropicolinamide and the whole isheated on a steam bath until the development of gaseous N 0, which setsin immediately, ceases. The cooled solution is neutralised with asaturated solution of hydrogen chloride in ether and concentrated invacuo. The residue is distributed between water and ether and the ethersolution is separated, dried and concentrated. After crystallisation ofthe residue from isopropanol 3-hydroxy-N-methyl-picolinamide is formedin the form of colourless crystals having a melting point of 6667.

In an analogous manner the following amides of 3- hydroxy-picolinic acidare obtained:

N-benzyl-amide, M.P. 84 (from isopropanol);

N-cyclohexyl-amide hydrochloride, M.P. 215 (from methanol-acetone)N-(sec. butyl)-amide hydrochloride, M.P. 131134 (from isopropanol);

N-n-butyl-amide, B.P. 0,0002 106109, M.P. below 20;

N-ethyl-amide hydrochloride, M.P. 156-l58 (from isopropanol);

N-n-propyl-amide hydrochloride, M.P. 151-154 (from isopropanol)N-m-amyl-amide hydrochloride, M.P. 149152 (from isopropanol);

N-isoamyl-amide, B.P. 104;

N-n-dodecyl-amide hydrochloride, M.P. 135 (from isopropanol);

N-allyl-amide hydrochloride, M.P. 140-143 (from isopropanol);

N-propargyl-amide, M.P. 84 (from isopropanol);

N-(fi-dimethylaminoethyl) amide hydrochloride, M.P.

187189 (from isopropanol);

N-(,B-diethylaminoethyl) amide, M.P. l48l50 (from acetone);

N-(y-dimethylaminopropyl) amide,

(from methanol-isopropanol);

N-[B-(2'-pyridyl)-ethyl] amide, M.P. 72 (from isopropanol);

N-[B-(4'-pyridyl)-ethyl] amide, M.P. 90.59l.5 (from ethyl acetate);

N-(3,5-dimethylbenzyl) amide, M.P. 63-64 (from acetone-water)N-(m-trifluoromethylbenzyl) amide hydrochloride, M.P.

157-l6l (from isopropanol);

N-(2,4-dichlorobenzyl) amide, M.P. 107.5 (from isopropanol);

N-(3,4-dichlorobenzyl) amide, M.P. 98 (from isopropanol);

N-(3,4,5-trimethoxybenzyl) amide, M.P. 124

acetone);

(from N-(3,4-dimethoxybenzyl) amide, M.P. 86-88 (isopropanol-ether)N-(o-chlorobenzyl) amide, M.P. 9496 (from isopropanol);

N-(B-carbethoxyethyl) amide, B.P. 0,004 127-129";

N-cyanomethyl amide, M.P. 132 (from isopropanol);

N-carbethoxymethyl amide, M.P. 87.588 (from isopro-N-(B-piperidinoethyl) amide, hydrochloride, M.P. 213- 214 (fromisopropanol);

N-(v-carbethoxypropyl) amide, 121123 (from isopropanol);

N-(p-chlorobenzyl) amide, M.P. 99100 (from isopropanol);

N-(m-fluorobenzyl) amide, M.P. 53

panol);

N-(o-nitrobenzyl) amide, M.P. 139140 (from dioxan);

N-(m-nitrobenzyl) amide, M.P. 117123 (from chloroform);

N-(p-nitrobenzyl) amide, M.P. 128-129 (from acetoneisopropanol)N-(o-methylbenzyl) amide, M.P. 76

panol);

N-(m-methylbenzyl) amide, hydrochloride, M.P. 176- 179 (fromdioxan-isopropanol);

N-(p-methylbenzyl) amide, M.P. -81 (from isopropanol);

N-(o-methoxybenzyl) amide, M.P. 7172 (from ether);

N-(m-methoxybenzyl) amide, hydrochloride, M.P. 16l- 162 (frommethanol-ether);

N-(p-methoxybenzyl) amide, M.P. 94 (from isopropanol);

N-(p-tert. butylbenzyl) amide, M.P. 84 (from ethanol);

N-(B-phenylethyl) amide, M.P. 31-32 (from ethanol);

N-[B-(p-nitrophenyD-ethyl] amide, M.P. 184-186 (from dioxan);

N-(y-phenylpropyl) amide, hydrochloride, M.P. 141- 143 (fromisopropanol);

N- ['Y- (p-nitrophenyl) -propyl] (from isopropanol);

N-cinnamyl amide [N-(v-phenylallyl) amide], M.P. 77-

79 (from isopropanol);

N-(y-phenoxypropyl) amide, hydrochloride, M.P. 148- 152 (fromdioxan-ether);

N-furfuryl amide, M.P. 60 (from isopropanol);

N-piperidinocarbonylmethyl amide, M.P. 117 (from isopropanol-dioxan)hydrochloride, M.P.

(from isopro- (from isoproamide, M.P. 107109 Example 4 A mixture of 5.00g. of 3-hydroxy-N-nitro-picolinamide, 5.0 g. of aniline and 10 ml. ofdimethyl formamide is heated in an oil bath until gas evolution takesplace. (Reaction temperature 80-100"). After termination of the gasdevelopment, the reaction mixture is cooled, water is added and theexcess aniline distilled off with steam. The crystals which precipitateafter cooling are extracted with methylene chloride-ether, the organicphase is dried and concentrated. On dissolving and recrystallising theresidue from isopropanol, 3-hydroxy-N- phenyl-picolinamide is obtainedin the form of crystals having a melting point of 8889.

In an analogous manner, the following compounds are produced, thereaction (gas evolution) occurs at the temperature indicated in bracketsafter each compound:

3-hydroxy-N-(p-methylphenyl) picolinamide (75-80),

M.P. 89 (from isopropanol);

3-hydroxy-N-(m-methylphenyl) picolinamide (75-85 M.P. 66-68 (fromisopropanol) 3-hydroxy N (o methylphenyl) picolinamide (110- 120"), M.P.90-92 (from isopropanol);

3-hydroxy N (m chlorophenyl) picolinamide M.P. 131 (from isopropanol);and

3-hydroxy-N-methyl-N-phenyl-picolinamide M.P.

149-151 (from isopropanol) 7 Example 5 A mixture of 15.0 ,g. of 3hydroxy-N-nitro-picolin amide, 20.0 g. of p-anisidine and 30 ml. ofdimethyl formamide is heated in an oil bath until gas evolution takesplace (reaction temperature 65-75"). When the development of gas hasceased, the reaction mixture is cooled, then cooled to after addition'ofwater, and filtered. On dissolving and recrystallising the filter resi-'due from isopropanol, 3-hydroxy-N-(p-methoxyphenyl)- picolinamide isobtained as colourless crystals having a melting point of 108.

3-hydroxy-N-(p-dimethylaminophenyl) picolinamide, M.P. 109-1 10 (fromisopropanol) is produced in the same manner, using an equimolar amountof the corresponding amine instead of anisidine.

Example 6 A mixture of 5.0 g. of 3-hydroxy-N-nitro-picolinamide,

.7.5 g. of p-nitraniline and 10 ml. of dimethyl forrnamide is heated inan oil bath until gas evolution takes place (reaction temperature 150).After the development of gas has ceased, the reaction mixture is cooledand water and ether are added. The precipitated crystals are filteredand washed alternately with ether and water, whereby3-hydroxy-N-(p-nitrophenyl)-picolinamide is obtained as yellow crystalshaving a melting point of 252253.

In an analogous manner are obtained:

3-hydroxy-N-(o-chlorophenyl)-picolinamide, M.P. 118

(from isopropanol);

S-hydroxy-N-(3',4'-dichlorophenyl) picolinamide, M.P.

189 (from dioxan);

3-hydroxy-N-(2,4 dichlorophenyl) picolinamide, M.P.

188 (from chloroform-ethyl acetate);

3-hydroxy-N-(2,5 dichlorophenyl) picolinamide, M.P.

152 (from acetone);

S-hydroxy-N-(p-bromophenyl)-picolinamide, M.P. 150

(from isopropanol) and 3-hydroxy-N,N dimethyl picolinamide, M.P. 99-100(from isopropanol). 7

Example 7 2.0 g. of 3-hydroxy-N-nitro-picolinamide are added to m1. ofpiperidine and the mixture is heated on a steam bath until gas evolutionceases. It is then concentrated in vacuo, the residue is dissolved witha small amount of water, the solution is adjusted to a pH of about 4with concentrated hydrochloric acid and cooled to 0. The precipitatedcrystals are filtered, washed with a small volume of water and dissolvedand recrystallised from isopropanol yielding 3-hydroxy-picolinic acidpiperidide having a melting point of 162164.

3-hydroxy-picolinic acid morpholide with a melting point of 158 (fromisopropanol) is obtained in the same manner using an equivalent amountof morpholine instead of piperidine.

Example 8 A mixture of 10.0 g. of 3-hydroxy-N-nitro-picolinamide and ml.of aniline is heated in an oil bath between 60-80 until gas evolutionceases. Water is added to the reaction mixture and the excess aniline isdistilled with steam. The crystals which precipitate on cooling areextracted with ether and the ether solution is dried and concentrated.The residue is dissolved and recrystallised from isopropanol yielding3-hydroxy-N-phenyl-picolinamide; M.P. 88-89.

Example 9 A mixture of 10.0 g. of 3-hydroxy-N-nitro-picolinamide and20.0 g. of 2-amino-pyridine is heated in an oil bath between 130 and 140until gas evolution ceases. After cooling and addition of water, thereaction mixture is cooled to 0 and the precipitated crystals of3-hydroxy- N-(2'-pyridyl)-picolinamide are dissolved and recrystallizedfrom acetone-water. M.P. 88-90".

8 Example 10 A mixture of 25.0 g. of 3-hydroxy-N-nitro-picolinamide,16.5 g. of o-phenylene diamine and 50 ml. of dimethyl formamide isheated in an oil bath until gas evolution occurs (90) and the reactionis completed by gradually increasing the bath temperature to 130. Thered-brown solution is concentrated in vacuo,-water is added to theresidue which is filtered after cooling to 0. Crystallization fromisopropanol yield-s 3-hydroxy-N-(oaminophenyl)-picolinamide melting at125128.

In an analogous manner the following compounds are obtained. (Thetemperature at the beginning ofthe gas development and at the end of thereaction is indicated in brackets):

3-hydroxy-N (o hydroxyphenyl) picolinamide (100- 3-hydroxy-N-(o mercaptophenyl) picolinamide (90- 120"), and

3-hydroxy-N-(2' amino 4 methylphenyl) picolinamide (110-120").

Example 11 14.0 g. of 3-hydroxy-N-(o-amino-phenyl)-picolinarnide isheated under a stream of nitrogen at 210240 C. until evolution of waterceases. The resulting black residue is recrystallized from ethyl acetatefurnishing 9.8 g. of 2-[2'-(3'-hydroxy-pyridyl)]-benzimidazole; M.P.187- 188.

Example 12 In an analogous manner 2-[2'-(3'-hydroxy-pyridyl)]-benzothiazole, M.P. 150, is obtained by cyclizing 3- hyd roxy-N-(o-mercapto-phenyl) -picolinamide;

2 [2- (3'-hydroxy-pyridyl)]-5-chloro-benzothiazole by cyclizing3-hydroxy N (2'-mercapto-5'-chloro-phenyl)- picolinamide;

2 [2'-(3'-hydroxy-pyridyl) ]-5-nitro-benzimidazo1e by cyclizing3-hydroxy-N-(2'-amino-5-nitro-phenyl)pico1inamide;

2-[2'-(3'-hydroxy-pyridy1)] 5 methoxy-benzothiazole by cyclizing3-hydroxy-N-(2-mercapto-5'-methoxy-phenyl)-picolinamide;

2- 2'-( 3'-hydroxy-pryidyl) ]-4-methyl-benzimidazole by cyclizing3-hydroXy-N-(2'-amino-4-methyl-phenyl) -picolinamide; and

l-methyl-Z- [2-( 3 -hydroxy-pyridyl) ]-benzimidazole by cyclizing3-hydroxy-N-(2 methylamino-phenyl -picolinamide; and also the analogousS-bromo and S-fiuoro benzothiozoles, benzimidazoles and benzoxazoles bycyclization of the cor-responding 3-hydroxy-N(2'-hydroxy-, 2'-mercaptoand 2'-amino-phenyl-picolinamides which are substiuted in5-position at the phenyl ring by bromine or fluorine, respectively.

We claim:

1. The compound of the formula CO-NH-Nor N 5. Acompound of the formula Yis a member selected from the group consisting of Cl, Br, F, N0 loweralkyl and lower alkoxy.

References Cited by the Examiner OH X I Y N Q 5 Eastwood et al.: J.Chem. Soc. (1960), pp. 2286-92. wherein: Habib et al.: J. Chem. Soc.(1960), pp. 3371-83.

X is a member selected from the group consisting of OH and 1 alkyl, andWALTER A. MODANCE, Primary Examiner.

1. THE COMPOUND OF THE FORMULA
 5. A COMPOUND OF THE FORMULA